Abstract

The Kv11.1 potassium channel is the molecular target for the majority of drugs implicated in acquired long QT syndrome (aLQTS), the commonest cause of drug-induced sudden cardiac death, and a common reason for drug restriction or withdrawal from the market. Whilst the IC50 for block of Kv11.1 is commonly used to estimate the risk of aLQTS, this approach is crude and it is widely accepted that the kinetics of drug interactions with the channel are a critical component in understanding their mechanism of action and risk profiles. In this study we report the first directly measured kinetics of block and unblock of Kv11.1 by a QT prolonging drug - the antipsychotic clozapine. Our data show that clozapine binding to Kv11.1 is complex. There are at least two kinetically distinct components to both block and unblock while the kinetics of unblock are dependent on the dose or duration of drug application. Based on these observations we have proposed a model incorporating kinetically distinct binding to the open and inactivated states of Kv11.1 that can describe the observed kinetic features of clozapine block and correctly predict the overall affinity and apparent non-state dependent interaction of clozapine with Kv11.1. Mechanistic insights into drug block of Kv11.1, gained though detailed kinetic analysis such as this, have a potential role in development of drugs targeted to specific channel states to reduce unwanted side effects as well as in the design of better high throughput preclinical tests for assessing the proarrhythmic effects of QT prolonging drugs.